PROJECT 2: EFFECTS OF DOCOSAHEXAENOIC ACID (DMA) IN SLOWING THE PROGRESSION OF ALZHEIMER'S DISEASE Abundant evidence from epidemiologic studies and animal studies supports the choice of DMA, an omega-3 fatty acid, as a treatment for Alzheimer's disease (AD). Epidemiologic studies show a reduced risk of AD associated with DMA consumption, and studies in murine models of AD show that dietary DMA reduces brain levels of beta amyloid (Ap), Ap-mediated oxidative damage, and neurotoxicity. We propose a multicenter, double-blind, placebo-controlled, parallel arm clinical trial of DMA to slow the progression of Alzheimer's disease (AD). Participation will be limited to subjects consuming less than 200mg DMA per day, or 300% of the amount of DMA in the average American diet. A dose of 2 grams per day is proposed, based on evidence that plasma levels of DMA are increased to maximum levels in most subjects by this dose, and based on evidence that this dose is safe. A population of 400 subjects will be studied, with 60% (n=240) assigned to active treatment, and 40% (n=160) assigned to placebo. The disproportionate randomization to active treatment is intended to enhance recruitment. The treatment period will continue for 18 months. The dual primary endpoints are rate of decline on the ADAS-cog and rate of decline on CDR-SOB. Functional and behavioral effects of treatment will also be assessed. Compliance with study drug, other relevant changes in diet, and the hypothesized therapeutic mechanisms will be assessed in this trial using a panel of biomarkers. Serial plasma levels of DMA will be used to monitor compliance with supplementation, variability in absorption, and possible changes in dietary intake of DMA during the study. Based on animal studies, the hypothesized mechanisms of action of DMA include anti-amyloid, antioxidant, and neuroprotectant effects. Volumetric brain MRI determinations of brain atrophy rate in a sub-set of subjects will be used to detect neuroprotectant effects. Cerebrospinal fluid levels of beta amyloid (Ap) and lipid peroxidation products in a sub-set of subjects will be used to detect anti-amyloid and antioxidant effects. Plasma and urine markers of oxidative damage and plasma levels of AD-relevant micronutrients will also be obtained in order to monitor other changes in dietary habits which might confound detection of DMA effects. Based on a conservative estimate of rate of decline in the placebo group (3.8 points per year on the ADAScog, 67% of the placebo rate of decline in a recently completed ADCS trial) this study design will have 90% power to detect a 38% or larger reduction in the rate of ADAS-Cog decline between DMA and placebo, and 80% power to detect a 33% effect.